Compounds

ABSTRACT

The present invention relates to new compounds of formula (I) wherein Y, P, R 1 , R 2 , R 3 , n, m are defined as in claim 1, a process for their preparation and new intermediates used therein, pharmaceutical composition containing said therapeutically active compounds and to the use of said active compounds in therapy, especially in the prevention and/or treatment of dementia related disease, Alzheimer&#39;s Disease and conditions associated with glycogen synthase kinase-3.

FIELD OF THE INVENTION

The present invention relates to new compounds of formula I, as a freebase or salts thereof, to pharmaceutical composition containing saidcompounds and to the use of said compounds in therapy. The presentinvention further relates to processes for the preparation of compoundsof formula I and to new intermediates used in the preparation thereof.

BACKGROUND OF THE INVENTION

Glycogen synthase kinase 3 (GSK3) is a serine/threonine protein kinasecomposed of two is isoforms (α and β), which are encoded by distinctgenes but are highly homologous within the catalytic domain. GSK3 ishighly expressed in the central and peripheral nervous system. GSK3phosphorylates several substrates including tau, β-catenin, glycogensynthase, pyruvate dehydrogenase and elongation initiation factor 2b(eIF2b). Insulin and growth factors activate protein kinase B, whichphosphorylates GSK3 on the serine 9 residue and inactivates it.

Alzheimer's Disease (AD) Dementias, and Taupathies.

AD is characterized by cognitive decline, cholinergic dysfunction andneuronal death, neurofibrillary tangles and senile plaques consisting ofamyloid-β deposits. The sequence of these events in AD is unclear, butbelieved to be related. Glycogen synthase kinase 3β (GSK3β) or Tau (τ)phosphorylating kinase selectively phosphorylates the microtubuleassociated protein τ in neurons at sites that are hyperphosphorylated inAD brains. Hyperphosphorylated protein τ has lower affinity formicrotubules and accumulates as paired helical filaments, which are themain components that constitute neurofibrillary tangles and neuropilthreads in AD brains. This results in depolymerization of microtubules,which leads to dying back of axons and neuritic dystrophy.Neurofibrillary tangles are consistently found in diseases such as AD,amyotrophic lateral sclerosis, parkinsonism-dementia complex of Gaum,corticobasal degeneration, dementia pugilistica and head trauma, Down'ssyndrome, postencephalatic parkinsonism, progressive supranuclear palsy,Niemann-Pick's Disease and Pick's Disease. Addition of amyloid-β toprimary hippocampal cultures results in hyperphosphorylation of τ and apaired helical filaments-like state via induction of GSK3β activity,followed by disruption of axonal transport and neuronal death (Imahoriand Uchida., J. Biochem 121:179-188, 1997). GSK3β preferentially labelsneurofibrillary tangles and has been shown to be active in pre-tangleneurons in AD brains. GSK3 protein levels are also increased by 50% inbrain tissue from AD patients. Furthermore, GSK3β phosphorylatespyruvate dehydrogenase, a key enzyme in the glycolytic pathway andprevents the conversion of pyruvate to acetyl-Co-A (Hoshi et al., PNAS93:2719-2723, 1996). Acetyl-Co-A is critical for the synthesis ofacetylcholine, a neurotransmitter with cognitive functions. Thus, GSK3βinhibition may have beneficial effects in progression as well as thecognitive deficits associated with Alzheimer's disease and otherabove-referred to diseases.

Chronic and Acute Neurodegenerative Diseases.

Growth factor mediated activation of the PI3K /Akt pathway has beenshown to play a key role in neuronal survival. The activation of thispathway results in GSK30β inhibition. Recent studies (Bhat et. al., PNAS97:11074-11079 (2000)) indicate that GSK3β activity is increased incellular and animal models of neurodegeneration such as cerebralischemia or after growth factor deprivation. For example, the activesite phosphorylation was increased in neurons vulnerable to apoptosis, atype of cell death commonly thought to occur in chronic and acutedegenerative diseases such as Alzheimer's Disease, Parkinson's Disease,amyotrophic lateral sclerosis, Huntington's Disease and HIV dementia,ischemic stroke and head trauma. Lithium was neuroprotective ininhibiting apoptosis in cells and in the brain at doses that resulted inthe inhibition of GSK3β. Thus, GSK3 β inhibitors could be useful inattenuating the course of neurodegenerative diseases.

Bipolar Disorders (BD)

Bipolar Disorders are characterised by manic episodes and depressiveepisodes. Lithium has been used to treat BD based on its moodstabilising effects. The disadvantage of lithium is the narrowtherapeutic window and the danger of overdosing, that can lead tolithium intoxication. The recent discovery that lithium inhibits GSK3 attherapeutic concentrations has raised the possibility that this enzymerepresents a key target of lithium's action in the brain (Stambolic etal., Curr. Biol. 6:1664-1668, 1996; Klein and Melton; PNAS 93:8455-8459,1996). Inhibition of GSK3β may therefore be of therapeutic relevance inthe treatment of BD as well as in AD patients that have affectivedisorders.

Schizophrenia

GSK3 is involved in signal transduction cascades of multiple cellularprocesses, particularly during neural development. Kozlovsky et al (Am JPsychiatry 2000 May; 157(5):831-3) found that GSK3β levels were 41%lower in the schizophrenic patients than in comparison subjects. Thisstudy indicates that schizophrenia involves neurodevelopmental pathologyand that abnormal GSK3 regulation could play a role in schizophrenia.Furthermore, reduced β-catenin levels have been reported in patientsexhibiting schizophrenia (Cotter et al., Neuroreport 9:1379-1383(1998)).

Diabetes

Insulin stimulates glycogen synthesis in skeletal muscles via thedephosphorylation and thus activation of glycogen synthase. Underresting conditions, GSK3 phosphorylates and inactivates glycogensynthase via dephosphorylation. GSK3 is also over-expressed in musclesfrom Type II diabetic patients (Nikoulina et al., Diabetes 2000February; 49(2):263-71). Inhibition of GSK3 increases the activity ofglycogen synthase thereby decreasing glucose levels by its conversion toglycogen. GSK3 inhibition may therefore be of therapeutic relevance inthe treatment of Type I and Type II diabetes and diabetic neuropathy.

Hair Loss

GSK3 phosphorylates and degrades β-catenin. β-catenin is an effector ofthe pathway for keratonin synthesis. β-catenin stabilisation may be leadto increase hair development. Mice expressing a stabilised β-catenin bymutation of sites phosphorylated by GSK3 undergo a process resembling denovo hair morphogenesis (Gat et al., Cell 1998 Nov. 25;95 (5):605-14)).The new follicles formed sebaceous glands and dermal papilla, normallyestablished only in embryogenesis. Thus GSK3 inhibition may offertreatment for baldness.

Oral contraceptives

Vijajaraghavan et al. (Biol Reprod 2000 June; 62 (6):1647-54) reportedthat GSK3 is high in motile versus immotile sperm. Immunocytochemistryrevealed that GSK3 is present in the flagellum and the anterior portionof the sperm head. These data suggest that GSK3 could be a key elementunderlying motility initiation in the epididymis and regulation ofmature sperm function. Inhibitors of GSK3 could be useful ascontraceptives for males.

DISCLOSURE OF THE INVENTION

The object of the present invention is to provide compounds having aselective inhibiting effect at GSK3 as well as having a goodbioavailability.

Accordingly, the present invention provides a compound of formula I

wherein:

-   -   Y is CH when P is a 5 or 6 membered aromatic, saturated or        unsaturated ring containing atoms independently selected from C,        N, O or S;    -   Y is N when P is a 5 membered aromatic or 5 or 6 membered        saturated or unsaturated ring containing atoms independently        selected from C, N, O or S;    -   R¹ is hydrogen;    -   R² is hydroxy, halogeno, fluoromethyl, difluoromethyl,        trifluoromethyl, fluoromethoxy, difluoromethoxy,        trifluoromethoxy, cyano, amino, nitro, C₁₋₃alkyl, C₁₋₃alkoxy,        C₁₋₃alkanoyloxy, C₂₋₄alkanoyl, C₁₋₄-alkanoylamino,        C₁₋₄alkoxycarbonyl, C₁₋₄alkylthio, C₁₋₄alkylsulphinyl,        C₁₋₄alkylsulphonyl, carbamoyl, N—C₁₋₄alkylcarbamoyl,        N,N-di(C₁₋₄alkyl)carbamoyl, aminosulphonyl,        N—C₁₋₄alkylaminosulphonyl, N,N-di(C₁₋₄alkyl)aminosulphonyl,        C₁₋₄alkylsulphonylamino, or a group R⁴X¹,        -   wherein X¹ is a direct bond, C₂₋₄alkanoyl, CONR⁵R⁶, SO₂NR⁷R⁸            or SO₂R⁹ (wherein R⁵ and R⁷ each independently are hydrogen            or C₁₋₂alkyl and R⁶, R⁸ and R⁹ each independently are            C₁₋₄alkyl and wherein R⁴ is linked to R⁶, R⁸ or R⁹); and        -   R⁴ is phenyl or a 5 or 6 membered heterocyclic group with            one or two heteroatoms, selected independently from O, S and            N, which heterocyclic group may be saturated or unsaturated            and which phenyl or heterocyclic group may be substituted            with one or two substituents selected independently from            hydroxy, halogeno, C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkanoyloxy,            trifluoromethyl, cyano, amino, nitro and C₁₋₄alkoxycarbonyl;    -   R³is hydroxy, halogeno, nitro, fluoromethyl, difluoromethyl,        trifluoromethyl, fluoromethoxy, difluoromethoxy,        trifluoromethoxy, C₁₋₃alkyl, cyano, amino or R¹⁰X²,        -   wherein x² is O, CH₂, S, SO, SO₂, NR¹¹CO, CONR¹², SO₂NR¹³,            NR¹⁴SO₂ or NR¹⁵ (wherein R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ each            independently are hydrogen, C₁₋₃alkyl or            C₁₋₃alkoxyC₂-₃alkyl), or X² is a direct bond; and        -   R¹⁰ is selected from one of the following groups:        -   1) hydrogen or C₁₋₅alkyl which may be substituted with one            or more groups selected independently from hydroxy, fluoro            and amino;        -   2) C₁₋₅alkylX³COR¹⁶ (wherein X³ is O or NR¹⁷ (wherein R¹⁷ is            hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁶ is            C₁₋₃alkyl, NR¹⁸R¹⁹ or OR²⁰ (wherein R¹⁸, R¹⁹ and R²⁰ each            independently are hydrogen, C₁₋₃alkyl or            C₁₋₃alkoxyC₂₋₃alkyl));        -   3) C₁₋₅alkylX⁴R²¹ (wherein X⁴ is O, S, SO, SO₂, OCO, NR²²CO,            CONR²³, SO₂NR²⁴, NR²⁵SO₂ or NR²⁶ (wherein R²², R²³, R²⁴, R²⁵            and R²⁶ each independently are hydrogen, C₁₋₃alkyl or            C₁₋₃alkoxyC₂₋₃alkyl) and R²¹ is hydrogen, C₁₋₃alkyl,            cyclopentyl, cyclohexyl or a 5 or 6 membered saturated            heterocyclic group with one or two heteroatoms selected            independently from O, S and N, which C₁₋₃alkyl group may be            substituted with one or two substituents selected            independently from oxo, hydroxy, halogeno and C₁₋₄alkoxy and            which heterocyclic group may be substituted with one or two            substituents selected independently from oxo, hydroxy,            halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl and C₁₋₄alkoxy);        -   4) C₁₋₅alkylX⁵C₁₋₅alkylX⁶R²⁷ (wherein X⁵ and X⁶ each            independently are O, S, SO, SO₂, NR²⁸CO, CONR²⁹, SO₂NR³⁰,            NR³¹SO₂ or NR³² (wherein R²⁸, R²⁹, R³⁰, R³¹ and R³² each            independently are hydrogen, C₁₋₃alkyl or            C₁₋₃alkoxyC₂₋₃alkyl) and R²⁷ is hydrogen or C₁₋₃alkyl);        -   5) C₁₋₅alkylR³³ (wherein R³³ is a 5 or 6 membered saturated            heterocyclic group with one or two heteroatoms selected            independently from O, S and N, which heterocyclic group may            be substituted with one or two substituents selected            independently from oxo, hydroxy, halogeno, C₁₋₄alkyl,            C₁₋₄hydroxyalkyl and C₁₋₄alkoxy);        -   6) C₂₋₅alkenylR³³ (wherein R³³ is as defined hereinbefore);        -   7) C₂₋₅alkynylR³³ (wherein R³³ is as defined hereinbefore);        -   8) R³⁴ (wherein R³⁴ is a pyridone group, a phenyl group or a            5 or 6 membered aromatic heterocyclic group with 1 to 3            heteroatoms selected independently from O, N and S, which            pyridone, phenyl or heterocyclic group may carry up to 5            substituents selected independently from hydroxy, halogeno,            amino, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,            C₁₋₄aminoalkyl, C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy,            cyano, CONR³⁵R³⁶ and NR³⁷COR³⁸ (wherein R³⁵, R³⁶, R³⁷ and            R³⁸ each independently are hydrogen, C₁₋₄alkyl or            C₁₋₃alkoxyC₂₋₃alkyl));        -   9) C₁₋₅alkylR³⁴ (wherein R³⁴ is as defined hereinbefore);        -   10) C₂₋₅alkenylR³⁴ (wherein R³⁴ is as defined hereinbefore);        -   11) C₂₋₅alkynylR³⁴ (wherein R³⁴ is as defined hereinbefore);        -   12) C₁₋₅alkylX⁷R³⁴ (wherein X⁷ is O, S, SO, SO₂, NR³⁹CO,            CONR⁴⁰), SO₂NR⁴¹, NR⁴²SO₂ or NR⁴³ (wherein R³⁹, R⁴⁰, R⁴¹,            R⁴² and R⁴³ each independently are hydrogen, C₁₋₃alkyl or            C₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ is as defined hereinbefore);        -   13) C₂₋₅alkenylX⁸R³⁴ (wherein X⁸ is O, S, SO, SO₂, NR⁴⁴CO,            CONR⁴⁵, SO₂NR⁴⁶, NR⁴⁷SO₂ or NR⁴⁸ (wherein R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷            and R⁴⁸ each independently are hydrogen, C₁₋₃alkyl or            C₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ is as defined hereinbefore);        -   14) C₂₋₅alkynylX⁹R³⁴ (wherein X⁹ is O, S, SO, SO₂, NR⁴⁹CO,            CONR⁵⁰, SO₂NR⁵¹, NR⁵²SO₂ or NR⁵³ (wherein R⁴⁹, R⁵⁰, R⁵¹, R⁵²            and R⁵³ each independently are hydrogen, C₁₋₃alkyl or            C₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ is as defined hereinbefore);            and        -   15) C₁₋₃alkylX¹⁰C₁₋₃alkylR³⁴ (wherein X¹⁰ is O, S, SO₂, SO₂,            NR⁵⁴CO, ONR⁵⁵, SO₂NR⁵⁶, NR⁵⁷SO₂ or NR⁵⁸ (wherein R⁵⁴, R⁵⁵,            R⁵⁶, R⁵⁷ and R⁵⁸ each independently are hydrogen, C₁₋₃alkyl            or C₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ is as defined hereinbefore);        -   16) R³³ (wherein R³³ is as defined hereinbefore); and        -   17) C₁₋₃alkylX¹⁰C₁₋₃alkylR³³ (wherein X¹⁰ and R³³ are as            defined hereinbefore));    -   n is 0, 1, 2, 3 or 4;    -   m is 0, 1, 2, 3 or 4;        as a free base or salts thereof.

One aspect of the invention relates to compounds of formula I, whereinR² is C₁₋₃alkyl, halogeno, cyano, nitro, carbamoyl,N—C₁₋₄-alkylcarbamoyl, aminosulfonyl, C₁₋₄alkoxycarbonyl or a groupR⁴X¹,

-   -   wherein X¹ is CONR⁵R⁶, (wherein R⁵ is hydrogen or C₁₋₂alkyl and        R⁶ is C₁₋₄alkyl and wherein R⁴ is linked to R⁶); and    -   n is 0, 1 or 2.

Another aspect of the invention provides for compounds of formula I,wherein R³ is R¹⁰X²,

-   -   wherein X² is O; and    -   R¹⁰ is selected from one of the following groups:    -   1) hydrogen or C₁₋₅alkyl;    -   3) C₁₋₅alkylX⁴R²¹ (wherein X⁴ is O or NR²⁶ (wherein R²¹ and R²⁶        each independently are hydrogen, C₁₋₃alkyl, cyclopentyl or        cyclohexyl));    -   4) C₁₋₅alkylX⁵C₁₋₅alkylX⁶R²⁷ (wherein X⁵ and X⁶ are O and R²⁷ is        hydrogen or C₁₋₃alkyl);    -   5) C₁₋₅alkylR³³ (wherein R³³ is a 5 or 6 membered saturated        heterocyclic group with one or two heteroatoms selected        independently from O, S and N);    -   9) C₁₋₅alkylR³⁴ (wherein R³⁴ is a 5 or 6 membered aromatic        heterocyclic group with 1 to 3 heteroatoms selected        independently from O, N and S, which heterocyclic group may        carry up to 5 substituents selected independently from halogeno,        amino, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl,        C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy, hydoxy, cyano,        CONR³⁵R³⁶ and NR³⁷COR³⁸ (wherein R³⁵, R³⁶, R³⁷ and R³⁸ each        independently are hydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl));    -   17) C₁₋₃alkylX¹⁰C₁₋₃alkylR³³ (wherein X¹⁰ is O and R³³ is a 5 or        6 membered saturated heterocyclic group with one or two        heteroatoms selected independently from O, S and N);    -   m is 0, 1 or 2.

In a further aspect of the invention the following compounds areprovided:

-   3-[6-(2-Methoxyethoxy)isoquinolin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile,-   3-{6-[2-(2-Methoxyethoxy)ethoxy]isoquinolin-1-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile,-   2-Hydroxy-3-thieno[2,3-d]pyrimidin-4-yl-l1H-indole-5-carboxylic acid    methyl ester, and-   2-Hydroxy-3-(5,6,7,8-tetrahydroquinazolin-4-yl)-1H-indole-5-carboxylic    acid methyl ester;    as a free base or salts thereof, and-   3-{6-[2-(2-Methoxyethoxy)ethoxy]isoquinolin-1-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile    trifluoroacetate.

Listed below are definitions of various terms used in the specificationand claims to describe the present invention.

For the avoidance of doubt it is to be understood that where in thisspecification a group is qualified by ‘hereinbefore defined’ or ‘definedhereinbefore’ the said group encompasses the first occurring andbroadest definition as well as each and all of the preferred definitionsof that group.

For the avoidance of doubt it is to be understood that in thisspecification ‘C₁₋₅’ means a carbon group having 1, 2, 3, 4 or 5 carbonatoms.

In this specification, unless stated otherwise, the term “alkyl”includes both straight and branched chain alkyl groups. C₁₋₅alkyl may bemethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl,n-pentyl, i-pentyl, t-pentyl, neo-pentyl.

The term “alkoxy” as used herein, unless stated otherwise includes“alkyl”O groups in which “alkyl” is as hereinbefore defined. C₁₋₅alkoxymay be methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy,s-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, t-pentyloxy,neo-pentyloxy.

The term “alkanoyl” as used herein, unless otherwise stated includesformyl and alkylC═O groups in which “alkyl” is as defined hereinbefore,for example C₂alkanoyl is ethanoyl and refers to CH₃C═O, C₁alkanoyl isformyl and refers to CHO.

In this specification, unless stated otherwise, the term “alkenyl”includes both straight and branched chain alkenyl groups but referencesto individual alkenyl groups such as 2-butenyl are specific for thestraight chain version only. Unless otherwise stated, the term “alkenyl”advantageously refers to chains with 2 to 5 carbon atoms, preferably 3to 4 carbon atoms.

In this specification, unless stated otherwise, the term “alkynyl”includes both straight and branched chain alkynyl groups but referencesto individual alkynyl groups such as 2-butynyl are specific for thestraight chain version only. Unless otherwise stated, the term “alkynyl”advantageously refers to chains with 2 to 5 carbon atoms, preferably 3to 4 carbon atoms.

In this specification, unless stated otherwise, the term “5 or 6membered aromatic, saturated or unsaturated ring containing atomsindependently selected from C, N, O or S” may be, but are not limitedto, furyl), isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl,imidazolyl, imidazolidinyl, imidazolinyl, morpholinyl, piperazinyl,piperidyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl,pyrrolinyl, thiophenyl, tetrahydropyranyl, thiomorpholinyl, cyclohexylor cyclopentyl.

In this specification, unless stated otherwise, the term “5 memberedaromatic or 5 or 6 membered saturated or unsaturated ring containingatoms independently selected from C, N, O or S” may be, but are notlimited to, furyl, isoxazolyl, isothiazolyl, oxazolyl, imidazolidinyl,imidazolinyl, imidazolyl, morpholinyl, piperazinyl, piperidyl,piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl,pyrrolyl, thiazolyl, thiophenyl, tetrahydropyranyl or thiomorpholinyl.

In this specification, unless stated otherwise, the term “5 or 6membered heterocyclic group with one or two heteroatoms selectedindependently from O, S and N, which heterocyclic group may be saturatedor unsaturated” includes both heteroaromatic rings and heterocyclicrings that are saturated. Examples of such heterocyclic groups includes,but are not limited to, furyl, isoxazolyl, isothiazolyl, oxazolyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl,thiazolyl, thienyl, imidazolyl, imidazolidinyl, imidazolinyl,morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl,pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl orthiomorpholinyl.

In this specification, unless stated otherwise, the term “5 or 6membered saturated heterocyclic group with one or two heteroatomsselected independently from O, S and N” may be, but are not limited to,imidazolidinyl, morpholinyl, piperazinyl, piperidyl, piperidonyl,pyrazolidinyl, pyrrolidinyl, tetrahydropyranyl or thiomorpholinyl.

In this specification, unless stated otherwise, the term “5 or 6membered aromatic heterocyclic group with 1 to 3 heteroatoms selectedindependently from O, N and S” may be, but are not limited to, furyl,imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, triazinyl,pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl orthienyl.

In this specification, unless stated otherwise, the term “5 or 6membered heterocyclic ring containing 1 to 3 heteroatoms selectedindependently from O, N and S” may be, but are not limited to, furyl,imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl or thienyl.

In this specification, unless stated otherwise, the term halogeno may befluor, chlorine, bromine or iodine.

For the avoidance of any doubt, it is to be understood that when X² is,for example, a group of formula NR¹¹CO, it is the nitrogen atom bearingthe R¹¹ group which is attached to the quinazoline ring and the carbonyl(CO) group is attached to R¹⁰, whereas when X² is, for example, a groupof formula CONR¹², it is the carbonyl group which is attached to thequinazoline ring and the nitrogen atom bearing the R¹² group is attachedto R¹⁰. A similar convention applies to the other two atoms X² linkinggroups such as NR¹⁴SO₂ and SO₂NR¹³. When X² is NR¹⁵ it is the nitrogenatom bearing the R¹⁵ group, which is linked to the quinazoline ring andto R¹⁰. An analogous convention applies to other groups. It is furtherto be understood that when X² represents NR¹⁵ and R¹⁵ isC₁₋₃alkoxyC₂₋₃alkyl it is the C₂₋₃alkyl moiety, which is linked to thenitrogen atom of X² and an analogous convention applies to other groups.

For the avoidance of any doubt, it is to be understood that in acompound of formula I when R¹⁰ is, for example, a group of formulaC₁₋₅alkylX¹⁰C₁₋₅alkylR³⁴, it is the terminal C₁₋₅alkyl moiety which islinked to X¹⁰, similarly when R¹⁰ is, for example, a group of formulaC₂₋₅alkenylR³⁴ it is the C₂₋₅alkenyl moiety which is linked to X² and ananalogous convention applies to other groups.

For the avoidance of any doubt, it is to be understood that when R³⁴carries a C₁₋₄aminoalkyl substituent it is the C₁₋₄alkyl moiety, whichis attached to R³⁴ whereas when R³⁴ carries a C₁₋₄alkylamino substituentit is the amino moiety, which is attached to R³⁹ and an analogousconvention applies to other groups.

For the avoidance of any doubt when X¹ is C₂₋₄alkanoyl it is thecarbonyl moiety, which is linked to the heteroaromatic oxindole groupand it is the alkyl moiety, which is linked to R⁴ and an analogousconvention applies to other groups.

The present invention relates to the use of compounds of formula I ashereinbefore defined as well as to the salts thereof. Salts for use inpharmaceutical compositions will be pharmaceutically acceptable salts,but other salts may be useful in the production of the compounds offormula I.

Both organic and inorganic acids can be employed to form non-toxicpharmaceutically acceptable acid addition salts of the compounds of thisinvention. In addition, a suitable pharmaceutically acceptable salt ofthe compounds of the invention is an alkali metal salt, an alkalineearth metal salt or a salt with an organic base.

Some compounds of formula I may have chiral centres and/or geometricisomeric centres (E- and Z-isomers), and it is to be understood that theinvention encompasses all such optical, diastereoisomers and geometricisomers that possess GSK3 inhibitory activity.

It is to be understood that the present invention also relates to anyand all tautomeric forms of the compounds of formula I.

Methods of Preparation

The present invention also relates to processes for preparing compoundsof formula I. Throughout the following description of such processes itis to be understood that, where appropriate, suitable protecting groupswill be added to, and subsequently removed from, the various reactantsand intermediates in a manner that will be readily understood by oneskilled in the art of organic synthesis. Conventional procedures forusing such protecting groups as well as examples of suitable protectinggroups are described, for example, in “Protective Groups in OrganicSynthesis” T. W. Greene, P. G. M. Wuts, Wiley-Interscience, New York,1999.Methods of Preparation of Intermediates

(i) Alkylation of a compound of formula II with a suitable alkylatingreagent e.g. R¹⁰-L¹, wherein R¹⁰ is defined as hereinbefore and L¹ is aleaving group such as a halogeno e.g. bromine, chlorine or an alkane- orarenesulfonyloxy group e.g. a p-toluenesulfonyloxy group, to form acompound of formula III may be carried out in a suitable solvent such asN,N-dimethylformamide, methylene chloride or acetonitrile in thepresence of a suitable base such as potassium carbonate or triethylamine and the reaction may occur at a temperature between +20° C. and+130° C.

(ii) Reaction of a compound of formula III with malonic acid to form acompound of formula IV may be carried out in a suitable solvent such aspyridine or collidine, in the presence of a suitable base such aspiperidine or morpholine, and the reaction may occur at a temperaturebetween +20° C. and +130° C., followed by the treatment with an suitableacid such as hydrochloric acid or sulfuric acid.

(iii) Cyclization of a compound of formula IV to a compound of formula Vmay be carried out by

-   a) converting the acid function in a compound of formula IV to the    corresponding acid chloride using an appropriate chlorinating    reagent such as thionyl chloride or oxalyl chloride, followed by    treatment with a suitable azide e.g. sodium azide in a suitable    solvent such as dioxane, tetrahydrofuran, water or mixtures thereof,    to form the corresponding acyl azide,    followed by,-   b) cyclization of the acyl azide compound to the compound of formula    V in a suitable solvent such as diphenyl ether, at a reaction    temperature between +150° C. and +260° C.

(iv) Conversion of a compound of formula V to a compound of formula VI,wherein L² is a suitable leaving group such as a halogeno e.g. chlorineor bromine, may be carried with a suitable halogenation reagent such asthionyl chloride, oxalyl chloride, phosphoric trichloride or aluminumtribromide, in a suitable solvent such as methylene chloride,chloroform, toluene or using the halogenation reagent neat.

Methods of Preparation of End products

Another object of the invention is a process for the preparation ofcompounds of general formula I and salts thereof by reacting a compoundof formula VI, wherein L² is a leaving group and wherein P, Y, R³ and nare as defined in general formula I, with a compound of formula VII,wherein R¹, R² and m are as defined in general formula I,

The reaction of the process may be carried out in an appropriate solventsuch as an ether e.g. tetrahydrofuran or 1,4-dioxan, an aromatichydrocarbon solvent such as toluene, or a dipolar aprotic solvent suchas N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidin-2-one or dimethylsulphoxide and the reaction isconveniently effected at a temperature in the range of +10 to +150° C.,preferably in the range of +20 to +90° C. The reaction is advantageouslyeffected in the presence of a base. Such a base may be choosen from thegroup of organic amine bases such as pyridine, 2,6-lutidine, collidine,4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholineor diazabicyclo[5.4.0]undec-7-ene, tetramethylguanidine or an alkalimetal or alkaline earth metal carbonate or hydroxide such as sodiumcarbonate, potassium carbonate, calcium carbonate, sodium hydroxide orpotassium hydroxide. Alternatively, such a base may be an alkali metalhydride such as sodium hydride, or an alkali metal or alkaline earthmetal amide such as sodium amide, sodium bis(trimethylsilyl)amide,potassium amide or potassium bis(trimethylsilyl)amide.

When it is desired to obtain the acid salt, the free base may be treatedwith an acid using a conventional procedure.

Intermediates

The present invention further relates to new intermediates and the useof these intermediates in the preparation of compounds of formula I asdefined hereinbefore.

In one aspect of the invention the intermediate is a compound of formulaVI

wherein:

-   -   L² is halogeno;    -   R¹⁰ is selected from one of the following groups:    -   1) hydrogen or C₁₋₅alkyl which may be substituted with one or        more groups selected independently from hydroxy, fluoro and        amino;    -   2) C₁₋₅alkylX³COR¹⁶ (wherein X³ is O or NR¹⁷ (wherein R¹⁷ is        hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁶ is        C₁₋₃alkyl, NR¹⁸R¹⁹ or OR²⁰ (wherein R¹⁸g, R¹⁹ and R²⁰ each        independently are hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl));    -   3) C₁₋₅alkylX⁴R²¹ (wherein X⁴ is O, S, SO, SO₂, OCO, NR²²CO,        CONR²³, SO₂NR²⁴, NR²⁵SO₂ or NR²⁶ (wherein R²², R²³, R²⁴, R²⁵ and        R²⁶ each independently are hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R²¹ is hydrogen, C₁₋₃alkyl,        cyclopentyl, cyclohexyl or a 5 or 6 membered saturated        heterocyclic group with one or two heteroatoms selected        independently from O, S and N, which C₁₋₃alkyl group may be        substituted with one or two substituents selected independently        from oxo, hydroxy, halogeno and C₁₋₄alkoxy and which        heterocyclic group may be substituted with one or two        substituents selected independently from oxo, hydroxy, halogeno,        C₁₋₄alkyl, C₁₋₄hydroxyalkyl and C₁₋₄alkoxy);    -   4) C₁₋₅alkylX⁵C₁₋₅alkylX⁶R²⁷ (wherein X⁵ and X⁶ each        independently are O, S, SO, SO₂, NR²⁸CO, CONR²⁹, SO₂NR³⁰,        NR³¹SO₂ or NR³² (wherein R²⁸, R²⁹, R³⁰, R³¹ and R³² each        independently are hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)        and R²⁷ is hydrogen or C₁₋₃alkyl);    -   5) C₁₋₅alkylR³³ (wherein R³³ is a 5 or 6 membered saturated        heterocyclic group with one or two heteroatoms selected        independently from O, S and N, which heterocyclic group may be        substituted with one or two substituents selected independently        from oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl and        C₁₋₄alkoxy);    -   6) C₂₋₅alkenylR³³ (wherein R³³ is as defined hereinbefore);    -   7) C₂₋₅alkynylR³³ (wherein R³³ is as defined hereinbefore);    -   8) R³⁴ (wherein R³⁴ is a pyridone group, a phenyl group or a 5        or 6 membered aromatic heterocyclic group with 1 to 3        heteroatoms selected independently from O, N and S, which        pyridone, phenyl or heterocyclic group may carry up to 5        substituents selected independently from hydroxy, halogeno,        amino, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl,        C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy, cyano, CONR³⁵R³⁶ and        NR³⁷COR³⁸ (wherein R³⁵, R³⁶, R³⁷ and R³⁸ each independently are        hydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl));    -   9) C₁₋₅alkylR³⁴ (wherein R³⁴ is as defined hereinbefore);    -   10) C₂₋₅alkenylR³⁴ (wherein R³⁴ is as defined hereinbefore);    -   11) C₂₋₅alkynylR³⁴ (wherein R³⁴ is as defined hereinbefore);    -   12) C₁₋₅alkylX⁷R³⁴ (wherein X⁷ is O, S, SO, SO₂, NR³⁹CO, CONR⁴⁰,        SO₂NR⁴¹, NR⁴²SO₂ or NR⁴³ (wherein R³⁹, R⁴⁰, R⁴¹, R⁴² and R⁴³        each independently are hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ is as defined hereinbefore);    -   13) C₂₋₅alkenylX⁸R³⁴ (wherein X⁸ is O, S, SO, SO, NR⁴⁴CO,        CONR⁴⁵, SO₂NR⁴⁶, NR⁴⁷SO₂ or NR⁴⁸ (wherein R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷ and        R⁴⁸ each independently are hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ is as defined hereinbefore);    -   14) C₂₋₅alkynylX⁹R³⁴ (wherein X⁹ is O, S, SO, SO₂, NR⁴⁹CO,        CONR⁵⁰, SO₂NR⁵¹, NR⁵²SO₂ or NR⁵³ (wherein R⁴⁹, R⁵⁰, R⁵¹, R⁵² and        R⁵³ each independently are hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ is as defined hereinbefore); and    -   15) C₁₋₃alkylX¹⁰C₁₋₃alkylR³⁴ (wherein X¹⁰ O, S, SO, SO₂, NR⁵⁴CO,        ONR⁵⁵, SO₂NR⁵⁶, NR⁵⁷SO₂ or NR⁵⁸ (wherein R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷ and        R⁵⁸ each independently are hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ is as defined hereinbefore);    -   16) R³³ (wherein R³³ is as defined hereinbefore); and    -   17) C₁₋₃alkylX¹⁰C₁₋₃alkylR³³ (wherein X¹⁰ and R³³ are as defined        hereinbefore).

In another aspect of the invention the intermediate is a compound offormula VI

wherein:

-   -   L² is halogeno;    -   R¹⁰ is selected from one of the following groups:    -   1) hydrogen or C₁₋₅alkyl;    -   3) C₁₋₅alkylX⁴R²¹ (wherein X⁴ is O or NR²⁶ (wherein R²¹ and R²⁶        each independently are hydrogen, C₁₋₃alkyl, cyclopentyl or        cyclohexyl));    -   4) C₁₋₅alkylX⁵C₁₋₅alkylX⁶R²⁷ (wherein X⁵ and X⁶ are O and R²⁷ is        hydrogen or C₁₋₃alkyl);    -   5) C₁₋₅alkylR³³ (wherein R³³ is a 5 or 6 membered saturated        heterocyclic group with one or two heteroatoms selected        independently from O, S and N);    -   9) C₁₋₅alkylR³⁴ (wherein R³⁴ is a 5 or 6 membered aromatic        heterocyclic group with 1 to 3 heteroatoms selected        independently from O, N and S, which heterocyclic group may        carry up to 5 substituents selected independently from halogeno,        amino, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl,        C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy, hydoxy, cyano,        CONR³⁵R³⁶ and NR³⁷COR³⁸ (wherein R³⁵, R³⁶, R³⁷ and R³⁸ each        independently are hydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl));    -   17) C₁₋₃alkylX¹⁰C₁₋₃alkylR³³ (wherein X¹⁰ is O and R³³ is a 5 or        6 membered saturated heterocyclic group with one or two        heteroatoms selected independently from O, S and N).

EXAMPLES

The invention will now be illustrated in the following non-limitingExamples.

Example 1 6-(2-Methoxyethoxy)isoquinolin-1-ol

To 3-(2-methoxyethoxy)benzaldehyde (7.35 g, 40.6 mmol) and pyridine (65mL) were added malonic acid (8.5 g, 81.7 mmol) and piperidine (4 mL,40.6 mmol). The resulting yellow solution was heated at 80° C. undernitrogen atmosphere. Gas evolved as the reaction proceeded. After 2.5 hthe reaction was allowed to cool down to room temperature and stirringwas continued over night. The reaction solution was concentrated invacuo to give an oil. The oil was stirred with ice and triturated byslow addition of hydrochloric acid (12 M, 13 mL). The resulting yellowprecipitate was filtered and washed with aqueous hydrochloric acid (2 M,3×20 mL). The pale yellow solid obtained was dried in vacuo to give 8.7g. The solid (8.7 g, 39.2 mmol) was dissolved in thionyl chloride (70mL) and N,N-dimethylformamide (5 mL) and was refluxed under nitrogenatmosphere over night. After 16 h, the reaction solution was cooled toroom temperature and concentrated in vacuo. The residue was taken up indioxane (15 mL) and the resulting solution was added dropwise to astirred solution of sodium azide (7.6 g, 118 mmol) in dioxane/water (26mL, 1:1) at 5° C. The obtained suspension was stirred for 50 min at 3°C. and ethyl acetate (100 mL) was added. The layers were separated andthe aqueous layer was extracted with ethyl acetate (2×75 mL). Thecombined organic layers were washed with water (20 mL) and brine (30mL), dried over magnesium sulphate and filtered. Diphenyl ether (30 mL)was added and the ethyl acetate was removed in vacuo. The acyl azidesolution in diphenyl ether was added during 15 min to diphenyl ether (70mL) at 215° C. The reaction solution was refluxed 2.5 h and then stirredat room temperature over night. To the reaction solution was addeddiethyl ether (100 mL) and the precipitate formed was filtered off andwashed with diethyl ether. The precipitate was taken up inmethanol/dichloromethane, adsorbed onto silica gel (30 g) and purifiedby flash chromatography (gradient:dichloromethane:methanol; 98:2→95:5).The product containing fractions were combined and concentrated to givea solid. The solid was triturated with diethyl ether, filtered and driedin vacuo to give 3.15 g (37% yield) of the title compound. MS m/z 200(M⁺+1).

Example 2 1-Chloro-6-(2-methoxyethoxy)isoquinoline

To 6-(2-methoxyethoxy)isoquinolin-1-ol (3.15 g, 14.4 mmol) was addedphosphorus trichloride (70 mL) under nitrogen atmosphere. The mixturewas heated at reflux giving a nearly opaque brown solution. After 2 h atreflux, the solution was concentrated in vacuo until 20 mL remained andpoured onto ice water (100 mL). The pH of the resulting mixture wasadjusted to 6.5 with the addition of solid potassium carbonate andextracted with dichloromethane (3×100 mL). The combined organic layerswere washed with water (50 mL) and brine (50 mL) and concentrated invacuo. The resulting tan solid was taken up in dichloromethane, adsorbedon silica gel and purified by flash chromatography(gradient:hexane/ethyl acetate, 60:40→40:60) to give, after drying invacuo, 2.73 g (80% yield) of the title compound as a pale yellow solid.MS(AP+), 238 (100, M⁺+1), 202 (33), 179 (33).

Example 33-[6-(2-Methoxyethoxy)isoquinolin-1-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

To a solution of 5-cyanooxindole (400 mg, 2.53 mmol) in anhydroustetrahydrofuran under nitrogen atmosphere was addedN,N,N′N′-tetramethylethylenediamine (764 mL, 5.06 mmol). The solutionwas cooled to −71° C. and lithium diisopropylamide (3.87 mL, 5.06 mmol,1.5 M in cyclohexane) was added slowly resulting in a vibrant yellowsolution. A solution of 1-chloro-6-(2-methoxyethoxy)isoquinoline (661mg, 2.78 mmol) in tetrahydrofuran (20 mL) was added and the reactionsolution was stirred for 30 min at −7.5° C. and for 30 min at roomtemperature. The reaction solution was then brought to reflux. After 7.5h, the reaction solution was cooled to room temperature and an aqueousammonium chloride solution was added. The resulting orange solution wasconcentrated in vacuo. Dichloromethane was added and the red-orangeprecipitate formed was filtered off. The layers were separated and theaqueous layer was extracted with dichloromethane (3×100 mL). Thecombined organic layers were washed with water (50 mL) and brine (50mL), dried over sodium sulphate, filtered and concentrated. The orangesolid obtained was combined with the red-orange precipitate and mixedwith methanol/dichloromethane. The precipitate was washed with methanol.The mother liquor was adsorbed on silica gel and purified by flashchromatography (gradient; dichloromethane/methanol, 99:1→97:3) to give30 mg product. The flash chromatography product was combined with theprecipitate and the solid was trituated with diethyl ether and dried invacua to give 463 mg (51% yield) of the title compound as an orangesolid: mp 214-219° C. MS (AP+) m/z 360 (M⁺+1).

Example 4 3-[2-(2-Methoxyethoxy)ethoxy]benzaldehyde

To a solution of 3-hydroxybenzaldehyde (5.0 g, 41 mmol) inN,N-dimethylformamide (100 mL) was added bromo-2-(2-methoxyethoxy)ethane(6.0 mL, 45 mmol) followed by addition of solid potassium carbonate (17g, 122 mmol). The resulting slurry was heated under nitrogen at 57° C.for 19 h. The reaction mixture was cooled to room temperature andfiltered. The filter cake was washed with methanol and the filtrate wasreduced in vacuo to ˜50 mL and poured into water (200 mL). The solutionwas acidified to pH˜4 with hydrochloric acid (1 M) and extracted withethyl acetate (3×150 mL). The combined organic layer was washed withaqueous copper sulphate (75 mL), water (100 mL) and brine (100 mL),dried over sodium sulphate, filtered and concentrated in vacuo to aviscous oil. The oil was dried in vacuo to give 9,3 g (99% yield) of thetitle compound as a tan oil. ¹HNMR (300 MHz, DMSO-d6, TFA-d) δ 9.98 (s,1 H), 7.51 (m, 2 H), 7.44 (s, 1 H), 7.30 (m, 1 H),4.18(t J=5 Hz, 2H),3.76(t, J=5 Hz, 2 H),3.60(t, J=5 Hz, 2 H),3.46(t, j=5 Hz, 2 H), 3.25(s, 3 H).

Example 5 3-{3-[2-(2-Methoxyethoxy)ethoxy]phenyl}Acrylic Acid

To a solution of 3-[2-(2-methoxyethoxy)ethoxy]benzaldehyde (9.18 g, 40.9mmol) in pyridine (70 mL) under nitrogen was added malonic acid (8.69 g,81.9 mmol) followed by piperidine (4.13 mL, 40.9 mmol). The reactionsolution was stirred for 3 h at 85° C. and left stirring over night atroom temperature. The reaction solution was concentrated to an oil andleft on high vacuum over night to remove the remaining pyridine. To theoil was added ice (120 g) and under vigorous stirring, concentratedhydrochloric acid (13 mL) was added. The mixture was extracted withmethylene chloride (3×65 mL) and the combined organic layer was washedwith water (60 mL) and brine (60 mL), dried over sodium sulphate,filtered and concentrated in vacuo. The resulting oil was dried in highvacuum to give 10.8 g (99% yield) of the title compound. ¹HNMR (300 MHz,DMSO-d6) δ 12.28 (br s, 1 H), 7.56(d, J=16 Hz, 1 H),7.28(m, 3H),6.99(dd,J=8 Hz, J=2 Hz, 1 H),6.56 (d, J=16 Hz, 1 H), 4.14 (t, J=5 Hz, 2 H), 3.75(t, J=5 Hz, 2 H), 3.60 (t, J=5 Hz, 2 H), 3.36 (t, J=5 Hz, 2 H), 3.25 (s,3 H).

Example 6 6-[2-(2-Methoxyethoxy)ethoxyl]-2H-isoquinolin-1-one

To 3-{3-[2-(2-methoxyethoxy)ethoxy]phenyl}acrylic acid (10.7 g, 40.4mmol) was added thionyl chloride (60 mL) and N,N-dimethylformamide (5mL) and the reaction solution was refluxed under nitrogen atmosphere for15 h. The reaction solution was dried, concentrated and the resultingoil was taken up in 1,4-dioxane (25 mL) and added dropwise during 15 minto a solution of sodium azide (7.87 g, 121 mmol) in water/dioxane (28mL, 1:1) at 0° C. The suspension was stirred 30 min at 0° C., afterwhich the precipitate was filtered off and washed with ethyl acetate.The filtrate was extracted with ethyl acetate (3×150 mL) and thecombined organic layer was washed with water (75 mL) and brine (75 mL),dried over sodium sulphate and filtered. The azide containing solutionvolume was reduced in vacuo, diphenyl ether (20 mL) was added and theremaining ethyl acetate was removed in vacuo. The diphenyl ethersolution of the azide was added dropwise during 20 min to hot diphenylether (65 mL, 230° C.) and the obtained solution was heated 2 h atreflux (˜260° C.) and then left stirring at room temperature over night.Hexane was added to the reaction solution and the product precipitatedout as a black oil. The oil was pre-absorbed on silica gel and purifiedby flash chromatography (solvent gradient:methanol/methylene chloride,2:98→4:96) giving, after concentration and drying of the appropriatefractions, 3.4 g (32% yield) of the title compound as a yellow solid. MS(AP+) m/z 264 (M⁺+1).

Example 7 1-Chloro-6-[2-(2-methoxyethoxy)ethoxy]isoquinoline

Phosphorus trichloride (60 mL) and6-[2-(2-methoxyethoxy)ethoxy]-2H-isoquinolin-1-one (3.38 g, 14.3 mmol)were stirred at reflux under nitrogen atmosphere for 2 h. The reactionsolution was cooled to room temperature and concentrated in vacuo until10 mL remained. The obtained oil was poured onto ice water (80 mL) andstirred for 1 h. The mixture was neutralized with addition of solidpotassium carbonate and extracted with methylene chloride (3×80 mL). Thecombined organic layer was washed with water (50 mL) and brine (50 mL),dried over sodium sulphate, filtered and concentrated. The obtained oilwas pre-absorbed on silica gel and purified by flash chromatography(gradient:hexane/ethyl acetate, 6:4→4:6). The appropriate fractions werepooled, concentrated and dried to give 1.24 g (30% yield) of the titlecompound as a waxy solid. MS (AP+) m/z 282 (M+1).

Example 83-{6-[2-(2-Methoxyethoxy)ethoxy]isoquinolin-1-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrileTrifluoroacetate

A suspension of sodium hydride (92 mg, 3.55 mmol, 95% powder) intetrahydrofuran (10 mL) was slowly added via a cannula to a solution of2-oxo-5-indolinecarbonitrile (292 mg, 1.85 mmol) intetrahydrofuran/N-methylpyrrolidinone (15 mL, 2:1) under nitrogenatmosphere. The reaction mixture was stirred at room temperature for 25min. A solution of chloro-6-[2-(2-methoxyethoxy)ethoxy]isoquinoline (400mg, 1.42 mmol) in tetrahydrofuran (10 mL) was added and the reactionsolution was stirred at room temperature over night. The reaction wasquenched by slow addition of hydrochloric acid (1 M) and concentrated invacuo to a slurry. The slurry was diluted with acetonitrile (5 mL) andpurified by prep RP-HPLC (Cl 8 2″ column, gradient:acetonitril/water,20:80→0:100+0.1% TFA). The appropriate fractions were pooled andlyophilized giving 193 mg (27% yield) of the title compound as an orangetrifluoroacetate salt. MS (AP+) m/z 404 (M+1).

Example 9 2-Hydroxy-3-thieno[2,3-d]pyrimidin-4-yl-1H-indole-5-carboxylicAcid Methyl Ester

Sodium tert-butoxide (40.3 mg, 0.42 mmol) and methyl2-oxo-5-indolinecarboxylate (17.6 mg, 0.092 mmol) inN-methylpyrrolidinone (1 mL) under nitrogen atmosphere were stirred for5 min at room temperature. A solution of 4-chlorothieno[2,3-d]pyrimidine(0.1 mL, 0.84 M, corresponding to 14.3 mg, 0.084 mmol) inN-methylpyrrolidinone was added and the reaction mixture was stirred atroom temperature over night. The reaction mixture was diluted with water(20 mL) and acidified with hydrochloric acid (1 M) and extracted withethyl acetate (2×15 mL). The combined organic layer was washed withbrine, dried with sodium sulphate, filtered and concentrated. The crudeproduct was triturated with methylene chloride to give 10 mg (36% yield)of the title compound as a bronze solid. MS (AP−) m/z 324 (M−1).

Example 102-Hydroxy-3-(5,6,7,8-tetrahydroquinazolin-4-yl)-1H-indole-5-carboxylicAcid Methyl Ester

The title compound was synthesized according to the procedure describedfor Example 9 using sodium tert-butoxide (48 mg, 0.5 mmol), methyl2-oxo-5-indolinecarboxylate (21 mg, 0.11 mmol) and4-chloro-5,6,7,8-tetrahydroquinazoline solution (0.1 mL, 1 M inN-methylpyrrolidinone, corresponding to 17 mg, 0.1 mmol; described in:Budesinsky Z., Roubinek F. Collect. Czech. Chem. Commun., 1964, 29,2341). The crude oil was purified on SCX-column pre-rinsed with methanolusing ethyl acetate, methylene chloride, methylene chloride/methanol1:1, and methanol/ammonia (2 M, aq) as elution solvents.

The product was triturated with diethyl ether and dried in high vacuumto give 7 mg (22% yield) of the title compound as a solid. MS (AP+) m/z324.1 (M+1).

Pharmaceutical Compositions

According to one aspect of the present invention there is provided apharmaceutical composition comprising a compound of formula I, as a freebase or salts thereof, for use in prevention and/or treatment ofdementia related diseases, Alzheimer's Disease and conditions associatedwith glycogen synthase kinase-3 and other conditions listed below.

The composition may be in a form suitable for oral administration, forexample as a tablet, pill, syrup, powder, granule or capsule, forparenteral injection (including intravenous, subcutaneous,intramuscular, intravascular or infusion) as a sterile solution,suspension or emulsion, for topical administration as an ointment, patchor cream or for rectal administration as a suppository.

In general the above compositions may be prepared in a conventionalmanner using pharmaceutically carriers or diluents.

Suitable daily doses of the compounds of formula I in the treatment of amammal, including man, are approximately 0.01 to 250 mg/kg bodyweight atperoral administration and about 0.001 to 250 mg/kg bodyweight atparenteral administration. The typical daily dose of the activeingredients varies within a wide range and will depend on variousfactors such as the relevant indication, the route of administration,the age, weight and sex of the patient and may be determined by aphysician.

Medical Use

Surprisingly, it has been found that the compounds defined in thepresent invention, as a free base or salts thereof, are useful intherapy. The compounds of the present invention are well suited forinhibiting glycogen synthase kinase-3 (GSK3). Accordingly, the compoundsof the present invention are expected to be useful in the preventionand/or treatment of conditions associated with glycogen synthasekinase-3 activity, i.e. the compounds may be used to produce aninhibitory effect of GSK3 in mammals, including man, in need of suchprevention and/or treatment.

GSK3 is highly expressed in the central and peripheral nervous systemand in other tissues. Thus, it is expected that compounds of theinvention are well suited for the prevention and/or treatment ofconditions associated with glycogen synthase kinase-3 in the central andperipheral nervous system. In particular, the compounds of the inventionare expected to be suitable in the manufacture of a medicament for theprevention and/or treatment of dementia related diseases and Alzheimer'sDisease.

The dementia related diseases are selected from the group consisting ofFrontotemporal dementia Parkinson's Type, Parkinson dementia complex ofGuam, HIV dementia, diseases with associated neurofibrillar tanglepathologies, predemented states, vascular dementia, dementia with Lewybodies, Frontotemporal dementia and dementia pugilistica. The compoundsof the invention are also expected to be suitable in the manufacture ofa medicament for the prevention and/or treatment of amyotrophic lateralsclerosis, corticobasal degeneration, Down syndrome, Huntington'sDisease, Parkinson's Disease, postencephelatic parkinsonism, progressivesupranuclear palsy, Pick's Disease, Niemann-Pick's Disease, stroke, headtrauma and other chronic neurodegenerative diseases, Bipolar Disease,affective disorders, depression, schizophrenia, cognitive disorders,hair loss and contraceptive medication.

The compounds of the invention are further expected to be suitable inthe manufacture of a medicament for the prevention and/or treatment ofMild Cognitive Impairment, Age-Associated Memory Impairment, Age-RelatedCognitive Decline, Cognitive Impairement No Dementia, mild cognitivedecline, mild neurocognitive decline, Late-Life Forgetfulness, memoryimpairment and cognitive impairment and androgenetic alopecia.

The present invention relates also to the use of a compound of formula Ias defined hereinbefore, in the manufacture of a medicament for theprevention and/or treatment of conditions associated with glycogensynthase kinase-3.

In the context of the present specification, the term “therapy” alsoincludes “prevention” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

The invention also provides for a method of prevention and/or treatmentof dementia related diseases, Alzheimer's Disease and conditionsassociated with glycogen synthase kinase-3 and other conditions listedabove comprising administering to a mammal, including man, in need ofsuch prevention and/or treatment a therapeutically effective amount of acompound of formula I, as hereinbefore defined.

Non-Medical use

In addition to their use in therapeutic medicine, the compounds offormula I as a free base or a salts thereof, are also useful aspharmacological tools in the development and standardisation of in vitroand in vivo test systems for the evaluation of the effects of inhibitorsof GSK3 related activity in laboratory animals such as cats, dogs,rabbits, monkeys, rats and mice, as part. of the search for newtherapeutics agents.

Pharmacology

Determination of ATP Competition in Scintillation Proximity GSK3β Assay.

GSK3β Scintillation Proximity Assay.

The competition experiments were carried out in duplicate with 10different concentrations of the inhibitors in clear-bottom microtiterplates (Wallac, Finland). A biotinylated peptide substrate,Biotin-Ala-Ala-Glu-Glu-Leu-Asp-Ser-Arg-Ala-Gly-Ser(PO₃H₂)-Pro-Gln-Leu(AstraZeneca, Lund), was added at a final concentration of 1 μM in anassay buffer containing 1 mU recombinant human GSK3β (Dundee University,UK), 12 mM morpholinepropanesulfonic acid (MOPS), pH 7.0, 0.3 mM EDTA,0.01% β-mercaptorethanol, 0.004% Brij 35 (a natural detergent), 0.5%glycerol and 0.5 μg BSA/25 μl. The reaction was initiated by theaddition of 0.04 μCi [γ-³³P]ATP (Amersham, UK) and unlabelled ATP at afinal concentration of 1 μM and assay volume of 25 μl. After incubationfor 20 minutes at room temperature, each reaction was terminated by theaddition of 25 μl stop solution containing 5 mM EDTA, 50 μM ATP, 0.1%Triton X-100 and 0.25 mg streptavidin coated Scintillation ProximityAssay (SPA) beads (Amersham, UK). After 6 hours the radioactivity wasdetermined in a liquid scintillation counter (1450 MicroBeta Trilux,Wallac). The inhibition curves were analysed by non-linear regressionusing GraphPad Prism, USA. The K_(m) value of ATP for GSK30β, used tocalculate the inhibition constants (K_(i)) of the various compounds, was20 μM.

The following abbreviations have been used: ATP Adenosine TriphophataseBSA Bovin Serum Albumin EDTA Ethylenediaminetetraacetic acid GSK3Glycogen synthase kinase 3 MOPS Morpholinepropanesulfonic acid SPAScintillation Proximity AssayResults

Typical K_(i) values for the compounds of the present invention are inthe range of about 0.001 to about 10,000 nM. Other values for K_(i) arein the range of about 0.001 to about 1000 nM. Further values for K_(i)are in the range of about 0.001 nM to about 300 nM.

1. A compound of formula I

wherein: Y is CH when P is a 5 or 6 membered aromatic, saturated orunsaturated ring containing atoms independently selected from C, N, O orS; Y is N when P is a 5 membered aromatic or a 5 or 6 membered saturatedor unsaturated ring containing atoms independently selected from C, N, Oor S; R¹ is hydrogen; R² is hydroxy, halogeno, fluoromethyl,difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, cyano, amino, nitro, C₁₋₃alkyl, C₁₋₃alkoxy,C₁₋₃alkanoyloxy, C₂₋₄alkanoyl, C₁₋₄alkanoylamino, C₁₋₄alkoxycarbonyl,C₁₋₄alkylthio, C₁₋₄alkylsulphinyl, C₁₋₄alkylsulphonyl, carbamoyl,N—C₁₋₄alkylcarbamoyl, N,N-di(C₁₋₄alkyl)carbamoyl, aminosulphonyl,N—C₁₋₄alkylaminosulphonyl, N,N-di(C₁₋₄alkyl)aminosulphonyl,C₁₋₄alkylsulphonylamino, or a group R⁴X¹, wherein X¹ is a direct bond,C₂₋₄alkanoyl, CONR⁵R⁶, SO₂NR⁷R⁸ or SO₂R⁹ (wherein R⁵ and R⁷ eachindependently are hydrogen or C₁₋₂alkyl and R⁶, R⁸ and R⁹ eachindependently are C₁₋₄alkyl; and wherein R⁴ is linked to R⁶, R⁸ or R⁹);and R⁴ is phenyl or a 5 or 6 membered heterocyclic group with one or twoheteroatoms, selected independently from O, S and N, which heterocyclicgroup may be saturated or unsaturated and which phenyl or heterocyclicgroup may be substituted with one or two substituents selectedindependently from hydroxy, halogeno, C₁₋₃alkyl, C₁₋₃alkoxy,C₁₋₃alkanoyloxy, trifluoromethyl, cyano, amino, nitro andC₁₋₄alkoxycarbonyl; R³ is hydroxy, halogeno, nitro, fluoromethyl,difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, C₁₋₃alkyl, cyano, amino or R¹⁰X², wherein X² is O,CH₂, S, SO, SO₂, NR¹¹CO, CONR¹², SO₂NR¹³, NR¹⁴SO₂ or NR¹⁵ (wherein R¹¹,R¹², R¹³, R¹⁴ and R¹⁵ each independently are hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) , or X² is a direct bond; and R¹⁰ is selected fromone of the following: 1) hydrogen or C₁₋₅alkyl which may be substitutedwith one or more groups selected independently from hydroxy, fluoro andamino; 2) C₁₋₅alkylX³COR¹⁶, (wherein X³ is O or NR¹⁷ (wherein R¹⁷ ishydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁶ is C₁₋₃alkyl,NR¹⁸R¹⁹ or OR²⁰ (wherein R¹⁸, R¹⁹ and R²⁰ each independently arehydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); 3) C₁₋₅alkylX⁴R²¹,(wherein X⁴ is O, S, SO, SO₂, OCO, NR²²CO, CONR²³, SO₂NR²⁴, NR²⁵SO₂ orNR²⁶ (wherein R²², R²³, R²⁴, R²⁵ and R²⁶ each independently arehydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²¹ is hydrogen,C₁₋₃alkyl, cyclopentyl, cyclohexyl or a 5 or 6 membered saturatedheterocyclic group with one or two heteroatoms selected independentlyfrom O, S and N, which C₁₋₃alkyl group may be substituted with one ortwo substituents selected independently from oxo, hydroxy, halogeno andC₁₋₄alkoxy; and which heterocyclic group may be substituted with one ortwo substituents selected independently from oxo, hydroxy, halogeno,C₁₋₄alkyl, C₁₋₄hydroxyalkyl and C₁₋₄alkoxy); 4)C₁₋₅alkylX⁵C₁₋₅alkylX⁶R²⁷, (wherein X⁵ and X⁶ each independently are O,S, SO, SO₂, NR²⁸CO, CONR²⁹, SO₂NR³⁰ , NR³¹SO₂ or NR³² (wherein R²⁸, R²⁹,R³⁰, R³¹ and R³² each independently are hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R²⁷ is hydrogen or C₁₋₃alkyl); 5) C₁₋₅alkylR³³,(wherein R³³ is a 5 or 6 membered saturated heterocyclic group with oneor two heteroatoms selected independently from O, S and N, whichheterocyclic group may be substituted with one or two substituentsselected independently from oxo, hydroxy, halogeno, C₁₋₄alkyl,C₁₋₄hydroxyalkyl and C₁₋₄alkoxy); 6) C₂₋₅alkenylR³³, (wherein R³³ is asdefined hereinbefore); 7) C₂₋₅alkynylR³³, (wherein R³³ is as definedhereinbefore); 8) R³⁴, (wherein R³⁴ is a pyridone group, a phenyl groupor a 5 or 6 membered aromatic heterocyclic group with 1 to 3 heteroatomsselected independently from O, N and S, which pyridone, phenyl orheterocyclic group may carry up to 5 substituents selected independentlyfrom hydroxy, halogeno, amino, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,C₁₋₄aminoalkyl, C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy, cyano,CONR³⁵R³⁶ and NR³⁷COR³⁸ (wherein R³⁵, R³⁶, R³⁷ and R³⁸ eachindependently are hydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); 9)C₁₋₅alkylR³⁴, (wherein R³⁴ is as defined hereinbefore); 10)C₂₋₅alkenylR³⁴, (wherein R³⁴ is as defined hereinbefore); 11)C₂₋₅alkynylR³⁴, (wherein R³⁴ is as defined hereinbefore); 12)C₁₋₅alkylX⁷R³⁴, (wherein X⁷ is O, S, SO, SO₂, NR³⁹CO, CONR⁴⁰, SO₂NR⁴¹,NR⁴¹SO₂ or NR⁴³ (wherein R³⁹, R⁴⁰, R⁴¹, R⁴² and R⁴³ each independentlyare hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ is as definehereinbefore); 13) C₂₋₅alkenylX⁸R³⁴, (wherein X⁸ is O, S, SO, SO₂,NR⁴⁴CO, CONR⁴⁵, SO₂NR⁴⁶, NR⁴⁷SO₂ or NR⁴⁸(wherein R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷ andR⁴⁸ each independently are hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)and R³⁴ is as defined hereinbefore); 14) C₂₋₅alkynylX⁹R³⁴ (wherein X⁹ isO, S, SO, SO₂, NR⁴⁹CO, CONR⁵⁰, SO₂NR⁵¹, NR⁵²SO₂ or NR⁵³ (wherein R⁴⁹,R⁵⁰, R⁵¹, R⁵² and R⁵³ each independently are hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl and R³⁴ is as defined hereinbefore); and 15)C₁₋₃alkylX¹⁰C₁₋₃alkylR³⁴, (wherein X¹⁰ is O, S, SO, SO₂, NR⁵⁴CO, ONR⁵⁵,SO₂NR⁵⁶, NR⁵⁷SO₂ or NR⁵⁸ (wherein R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷ and R⁵⁸ eachindependently are hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ isas defined hereinbefore); 16) R³³, (wherein R³³ is as definedhereinbefore); and 17) C₁₋₃alkylX¹⁰C₁₋₃alkylR³³, (wherein X¹⁰ and R³³are as defined hereinbefore)); and wherein n is 0, 1, 2, 3 or 4; and mis 0, 1, 2, 3 or 4; and the compound of Formula I is a free base or asalt thereof.
 2. A compound according to claim 1, wherein R² isC₁₋₃alkyl, halogeno, cyano, nitro, carbamoyl, N—C₁₋₄alkylcarbamoyl,aminosulfonyl, C₁₋₄alkoxycarbonyl or a group R^(4X) ¹, wherein X¹ isCONR⁵R⁶, (wherein R⁵ is hydrogen or C₁₋₂alkyl and R⁶ is C₁₋₄alkyl andwherein R⁴ is linked to R⁶); and n is 0, 1 or
 2. 3. A compound accordingto claim 1, wherein R³ is R¹⁰X², wherein X² is O; and R¹⁰ is selectedfrom the group consisting of one of the following groups: 1) hydrogen orC₁₋₅alkyl; 3) C₁₋₅alkylX⁴R²¹, (wherein X⁴ is O or NR²⁶ (wherein R²¹ andR²⁶ each independently are hydrogen, C₁₋₃alkyl, cyclopentyl orcyclohexyl)); 4) C₁₋₅alkylX⁵C₁₋₅alkylX⁶R²⁷, (wherein X⁵ and X⁶ are O andR²⁷ is hydrogen or C₁₋₃alkyl); 5) C₁₋₅alkylR³³, (wherein R³³ is a 5 or 6membered saturated heterocyclic group with one or two heteroatomsselected independently from O, S and N); 9) C₁₋₅alkylR³⁴, (wherein R³⁴is a 5 or 6 membered aromatic heterocyclic group with 1 to 3 heteroatomsselected independently from O, N and S, which heterocyclic group maycarry up to 5 substituents selected independently from halogeno, amino,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,C₁₋₄hydroxyalkoxy, carboxy, hydoxy, cyano, CONR³⁵R³⁶ and NR³⁷COR³⁸(wherein R³⁵, R³⁶, R³⁷ and R³⁸ each independently are hydrogen,C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); 17) C₁₋₃alkylX¹⁰C₁₋₃alkylR³³,(wherein X¹⁰ is O and R³³ is a 5 or 6 membered saturated heterocyclicgroup with one or two heteroatoms selected independently from O, S andN); and m is 0, 1 or
 2. 4. A compound which is3-[6-(2-Methoxyethoxy)isoquinolin-1-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile,3-{6-[2-(2-Methoxyethoxy)ethoxy]isoquinolin-1-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile,2-Hydroxy-3-thieno[2,3-d]pyrimidin-4-yl-1H-indole-5-carboxylic acidmethyl ester, and2-Hydroxy-3-(5,6,7,8-tetrahydroquinazolin-4-yl)-1H-indole-5-carboxylicacid methyl ester, as a free base or a salt thereof, and3-{6-[2-(2-Methoxyethoxy)ethoxy]isoquinolin-1-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitriletrifluoroacetate.
 5. A pharmaceutical composition comprising as activeingredient a therapeutically effective amount of the compound accordingto claim 1 in association with pharmaceutically acceptable carriers ordiluents.
 6. The pharmaceutical composition according to claim 5 for usein prevention and/or treatment of dementia related diseases, Alzheimer'sDisease and conditions associated with glycogen synthase kinase-3. 7.(Canceled)
 8. (Canceled)
 9. (Canceled)
 10. (Canceled)
 11. (Canceled) 12.(Canceled)
 13. A method of prevention and/or treatment of a conditionselected from the group consisting of dementia related diseases,Alzheimer's Disease and conditions associated with glycogen synthasekinase-3, comprising administering to a patient in need of suchprevention and/or treatment, a therapeutically effective amount of thecompound of formula I as defined in claim
 1. 14. A process for thepreparation of the compound of formula I according to claim 1,comprising: reacting a compound of formula VI, wherein L² is a leavinggroup and wherein P, Y, R³ and n are as defined in general formula I,with a compound of formula VII, wherein R¹, R² and m are as defined ingeneral formula I,

in an appropriate solvent at a temperature in the range of about +10 toabout +150° C., optionally in the presence of a base.
 15. A compound offormula VI

wherein: L² is halogeno; R¹⁰ is selected from one of the followinggroups: 1) hydrogen or C₁₋₅alkyl which may be substituted with one ormore groups selected independently from hydroxy, fluoro and amino; 2)C₁₋₅alkylX³COR¹⁶, (wherein X³ is O or NR¹⁷ (wherein R¹⁷ is hydrogen,C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁶ is C₁₋₃alkyl, NR¹⁸ R¹⁹ or OR²⁰(wherein R¹⁸, R¹⁹ and R²⁰ each independently are hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl)) 3) C₁₋₅alkylX⁴R²¹, (wherein X⁴ is O, S, SO, SO₂,OCO, NR²²CO, CONR²⁶, SO₂NR²⁴, NR²⁵SO₂ or NR²⁶ (wherein R²², R²³, R²⁴,R²⁵ and R²⁶ each independently are hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R²¹ is hydrogen, C₁₋₃alkyl, cyclopentyl,cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one ortwo heteroatoms selected independently from O, S and N, which C₁₋₃alkylgroup may be substituted with one or two substituents selectedindependently from oxo, hydroxy, halogeno and C₁₋₄alkoxy and whichheterocyclic group may be substituted with one or two substituentsselected independently from oxo, hydroxy, halogeno, C₁₋₄alkyl,C₁₋₄hydroxyalkyl and C₁₋₄alkoxy); 4) C₁₋₅alkylX⁵C₁₋₅alkylX⁶R²⁷, (whereinX⁵ and X⁶ each independently are O, S, SO, SO₂, NR²⁸CO, CONR²⁹, SO₂NR³⁰,NR³¹SO₂ or NR³² (wherein R²⁸, R²⁹, R³⁰, R³¹ and R³² each independentlyare hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁷ is hydrogen orC₁₋₃alkyl); 5) C₁₋₅alkylR³³, (wherein R³³ is a 5 or 6 membered saturatedheterocyclic group with one or two heteroatoms selected independentlyfrom O, S and N, which heterocyclic group may be substituted with one ortwo substituents selected independently from oxo, hydroxy, halogeno,C₁₋₄alkyl, C₁₋₄hydroxyalkyl and C₁₋₄alkoxy); 6) C₂₋₅alkenylR³³, (whereinR³³ is as defined hereinbefore); 7) C₂₋₅alkynylR³³, (wherein R³³ is asdefined hereinbefore); 8) R³⁴, (wherein R³⁴ is a pyridone group, aphenyl group or a 5 or 6 membered aromatic heterocyclic group with 1 to3 heteroatoms selected independently from O, N and S, which pyridone,phenyl or heterocyclic group may carry up to 5 substituents selectedindependently from hydroxy, halogeno, amino, C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy,carboxy, cyano, CONR³⁵R³⁶ and NR³⁷COR³⁸ (wherein R³⁵, R³⁶, R³⁷ and R³⁸each independently are hydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl) ); 9)C₁₋₅alkylR³⁴, (wherein R³⁴ is as defined hereinbefore); 10)C₂₋₅alkenylR³⁴, (wherein R³⁴ is as defined hereinbefore); 11)C₂₋₅alkynylR³⁴ (wherein R³⁴ is as defined hereinbefore); 12)C₁₋₅alkylX⁷R³⁴, (wherein X⁷ is O, S, SO, SO₂, NR³⁹CO, CONR⁴⁰, SO₂NR⁴¹,NR⁴²SO₂ or NR⁴³ (wherein R³⁹, R⁴⁰, R⁴¹, R⁴² and R⁴³ each independentlyare hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ is as definedhereinbefore); 13) C₂₋₅alkenylX⁸R³⁴, (wherein X⁸ is O, S, SO, SO₂,NR⁴⁴CO, CONR⁴⁵, SO₂NR⁴⁶, NR⁴⁷SO₂ or NR⁴⁸ (wherein R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷ andR⁴⁸ each independently are hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)and R³⁴ is as defined hereinbefore); 14) C₂₋₅alkynylX⁹R³⁴, (wherein X⁹is O, S, SO, SO₂, NR⁴⁹CO, CONR⁵⁰, SO₂NR⁵¹, NR⁵² SO₂ or NR⁵³ (whereinR⁴⁹, R⁵⁰, R⁵¹, R⁵² and R⁵³ each independently are hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ is as defined hereinbefore); 15)C₁₋₃alkylX¹⁰C₁₋₃alkylR³⁴, (wherein X¹⁰ is O, S, SO, SO₂, NR⁵⁴CO, ONR⁵⁵,SO₂NR⁵⁶, NR⁵⁷SO₂ or NR⁵⁸ (wherein R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷ and R⁵⁸ eachindependently are hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ isas defined hereinbefore); 16) R³³, (wherein R³³ is as definedhereinbefore); and 17) C₁₋₃alkylX¹⁰C₁₋₃alkylR³³, (wherein X¹⁰ and R³³are as defined hereinbefore).
 16. The compound according to claim 15,wherein: L² is halogeno; R¹⁰ is selected from one of the followinggroups: 1) hydrogen or C₁₋₅alkyl; 3) C₁₋₅alkylX⁴R²¹, (wherein X⁴ is O orNR²⁶, (wherein R²¹ and R²⁶ each independently are hydrogen, C₁₋₃alkyl,cyclopentyl or cyclohexyl)); 4) C₁₋₅alkylX⁵C₁₋₅alkylX⁶R²⁷, (wherein X⁵and X⁶ are O and R²⁷ is hydrogen or C₁₋₃alkyl); 5) C₁₋₅alkylR³³ (whereinR³³ is a 5 or 6 membered saturated heterocyclic group with one or twoheteroatoms selected independently from O, S and N); 9) C₁₋₅alkylR³⁴,(wherein R³⁴ is a 5 or 6 membered aromatic heterocyclic group with 1 to3 heteroatoms selected independently from O, N and S, which heterocyclicgroup may carry up to 5 substituents selected independently fromhalogeno, amino, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,C₁₋₄aminoalkyl, C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy, hydoxy,cyano, CONR³⁵R³⁶ and NR³⁷COR³⁸ (wherein R³⁵, R³⁶, R³⁸ and R³⁸ eachindependently are hydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); and 17)C₁₋₃alkylX¹⁰C₁₋₃alkylR³³, (wherein X¹⁰ is O and R³³ is a 5 or 6 memberedsaturated heterocyclic group with one or two heteroatoms selectedindependently from O, S and N).
 17. (Canceled)
 18. The method ofprevention and/or treatment according to claim 13, wherein the dementiarelated diseases are selected from the group consisting ofFrontotemporal dementia Parkinson's Type, Parkinson dementia complex ofGaum, HIV dementia, diseases with associated neurofibrillar tanglepathologies, predemented states, vascular dementia, dementia with Lewybodies, Frontotemporal dementia and dementia pugilistica.
 19. Theprocess according to claim 14, wherein the compound of formula VI hasthe following structure

wherein: L² is halogeno; R¹⁰ is selected from one of the followinggroups: 1) hydrogen or C₁₋₅alkyl which may be substituted with one ormore groups selected independently from hydroxy, fluoro and amino; 2)C₁₋₅alkylX³COR¹⁶, (wherein X³ is O or NR¹⁷ (wherein R¹⁷ is hydrogen,C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁶ is C₁₋₃alkyl, NR¹⁸R¹⁹ or OR²⁰(wherein R¹⁸, R¹⁹ and R²⁰ each independently are hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl)); 3) C₁₋₅alkylX⁴R²¹, (wherein X⁴ is O, S, SO, SO₂,OCO, NR²²CO, CONR²³, SO₂NR²⁴, NR²⁵SO₂ or NR²⁶ (wherein R²², R²³, R²⁴,R²⁵ and R²⁶ each independently are hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R²¹ is hydrogen, C₁₋₃alkyl, cyclopentyl,cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one ortwo heteroatoms selected independently from O, S and N, which C₁₋₃alkylgroup may be substituted with one or two substituents selectedindependently from oxo, hydroxy, halogeno and C₁₋₄alkoxy and whichheterocyclic group may be substituted with one or two substituentsselected independently from oxo, hydroxy, halogeno, C₁₋₄alkyl,C₁₋₄hydroxyalkyl and C₁₋₄alkoxy); 4) C₁₋₅alkylX⁵C₁₋₅alkylX⁶R²⁷, (whereinX⁵ and X⁶ each independently are O, S, SO, SO₂, NR²⁸CO, CONR²⁹, SO₂NR³⁰,NR³¹SO₂ or NR³² (wherein R²⁸, R²⁹, R³⁰, R³¹ and R³² each independentlyare hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁷ is hydrogen orC₁₋₃alkyl); 5) C₁₋₅alkylR³³, (wherein R³³ is a 5 or 6 membered saturatedheterocyclic group with one or two heteroatoms selected independentlyfrom O, S and N, which heterocyclic group may be substituted with one ortwo substituents selected independently from oxo, hydroxy, halogeno,C₁₋₄alkyl, C₁₋₄hydroxyalkyl and C₁₋₄alkoxy); 6) C₂₋₅alkenylR³³, (whereinR³³ is as defined hereinbefore); 7) C₂₋₅alkynylR³³, (wherein R³³ is asdefined hereinbefore); 8) R³⁴, (wherein R³⁴ is a pyridone group, aphenyl group or a 5 or 6 membered aromatic heterocyclic group with 1 to3 heteroatoms selected independently from O, N and S, which pyridone,phenyl or heterocyclic group may carry up to 5 substituents selectedindependently from hydroxy, halogeno, amino, C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy,carboxy, cyano, CONR³⁵R³⁶ and NR³⁷COR³⁸ (wherein R³⁵, R³⁶, R³⁷ and R³⁸each independently are hydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); 9)C₁₋₅alkylR³⁴, (wherein R³⁴ is as defined hereinbefore); 10)C₂₋₅alkenylR³⁴, (wherein R³⁴ is as defined hereinbefore); 11)C₂₋₅alkynylR³⁴, (wherein R³⁴ is as defined hereinbefore); 12)C₁₋₅alkylX⁷R³⁴, (wherein X⁷ is O, S, SO, SO₂, NR³⁹CO, CONR⁴⁰, SO₂NR⁴¹,NR⁴²SO₂ or NR⁴³ (wherein R³⁹, R⁴⁰, R⁴¹, R⁴² and R⁴³ each independentlyare hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ is as definedhereinbefore); 13) C₂₋₅alkenylX⁸R³⁴, (wherein X⁸ is O, S, SO, SO₂,NR⁴⁴CO, CONR⁴⁵, SO₂NR⁴⁶, NR⁴⁷SO₂ or NR⁴⁸ (wherein R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷ andR⁴⁸ each independently are hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)and R³⁴ is as defined hereinbefore); 14) C₂₋₅alkynylX⁹R³⁴ (wherein X⁹ isO, S, SO, SO₂, NR⁴⁹CO, CONR⁵⁰, SO₂NR⁵¹, NR⁵²SO₂ or NR⁵³ (wherein R⁴⁹,R⁵⁰, R⁵¹, R⁵² and R⁵³ each independently are hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ is as defined hereinbefore); 15)C₁₋₃alkylX¹⁰C₁₋₃alkylR³⁴, (wherein X¹⁰ is O, S, SO, SO₂, NR⁵⁴CO, ONR⁵⁵,SO₂NR⁵⁶, NR⁵⁷SO₂ or NR⁵⁸ (wherein R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷ and R⁵⁸ eachindependently are hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ isas defined hereinbefore); 16) R³³, (wherein R³³ is as definedhereinbefore); and 17) C₁₋₃alkylX¹⁰C₁₋₃alkylR³³, (wherein X¹⁰ and R³³are as defined hereinbefore).
 20. A method of prevention and/ortreatment of a medical condition selected from the group consisting ofamyotrophic lateral sclerosis, corticobasal degeneration, Down syndrome,Huntington's Disease, Parkinson's Disease, postencephelaticparkinsonism, progressive supranuclear palsy, Pick's Disease,Niemann-Pick's Disease, stroke, head trauma and other chronicneurodegenerative diseases, Bipolar Disease, affective disorders,depression, schizophrenia, cognitive disorders, hair loss andcontraceptive medication, the method comprising administering to amammal in need of such prevention and/or treatment, a therapeuticallyeffective amount of the compound of formula I as defined in claim
 1. 21.A method of prevention and/or treatment of a medical condition selectedfrom the group consisting of Mild Cognitive Impairment, Age-AssociatedMemory Impairment, Age-Related Cognitive Decline, Cognitive ImpairmentNo Dementia, mild cognitive decline, mild neurocognitive decline,Late-Life Forgetfulness, memory and cognitive impairment andandrogenetic alopecia, the method comprising administering to a mammalin need of such prevention and/or treatment, a therapeutically effectiveamount of the compound of formula I as defined in claim 1.